Propionic acid is a key intermediate in a variety of human metabolic pathways including catabolism of the amino acids isoleucine, valine, methionine and threonine derived from protein. A number of inherited metabolic disorders (orphan diseases), as well as nutritional deficiencies of vitamins in a broad spectrum of disease states, affect propionate metabolism. Thus a simple diagnostic test for deficient oxidation of 1-13C-propionic acid, administered orally, would have considerable utility in the non-invasive diagnosis and management of a significant number of patients with organic acidemias, biotin deficiencies (secondary to total parenteral nutrition), B12 deficiencies and anemia. The proposed Phase I program (under Topic 4, NIADDK Solicitation) will be directed towards establishing a Master Drug File for 1-13C-propionate and preparing a study protocol for submission to the FDA as part of a Notice for an Investigational New Drug. Emphasis will be placed on the methods for breath analysis and on data reduction procedures (test scoring) in the interpretation of interindividual differences in the conversion of 1-13C-propionate into 13CO2. The overall objective will be to compare the fractional excretion rate constants, peak excretion rate and cumulative excretion at various time intervals after tracer administration as a function of different oral doses in normal controls and in patients with diseases affecting propionate metabolism both before and after nutritional therapy. The clinical studies in which the breath tests method is to be validated are already underway as part of an IRB approved study at the Pediatrics Department at the University of California at San Diego so that breath test results obtained in this study can be placed into perspective with regard to the total clinical picture, including the results of in-vitro clinical chemistry tests for propionate metabolism. Thus, the Phase I program can be summarized as an effort to develop a utilization protocol and a test scoring algorithm for 13C-propionate metabolism in order to differentiate with high sensitivity and specificity between normals and patients with disorders of propionate metabolism.